2alpha, 16alpha-dimethyl-11beta, 17alpha, 21-trihydroxy-4-pregnene-3, 20-dione and derivatives thereof



United States Patent 0 202,160: DllVIETI-IYL 11fi,17oc,21 TRIHYDROXY 4 PREGNENE 3,20 DIONE AND DERIVATIVES THEREOF Frank H. Lincoln, Kalamazoo, and William P. Schneider,

Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Filed Sept. 25, 1958, Ser. No. 763,196

r 4 Claims. (Cl. 260-397.45) This invention relates to certain novel steroids, more particularly to 2a,16a-dimethyl-1 1 9,17 a,21-trihydroxy-4- 3,251,866 Patented May 17, 1966 ICC pregnene-3,'20-dione, 2u,16a dimethyl-17a,21-dihydroxy- 4-pregnene 3,11,20 trione, 2a,16a-dimethyl-11B,17a,21- trihydroxy-1,4-pregnadiene-3,20-dione, 20:,160: dimethyl- 17m,21-dihydroxy-1,4-pregnadiene 3,11,20-trione, the corresponding 9u-halo, especially the 9a-fluoro compounds, 21 esters of each and intermediates in the production thereof, and to a process for their production. These compounds and a process for their production may 11 illustrated by the following formulae:

I iv) of ,--CH: OM CH (XVIII) CH; CH3

--0I1 0 H HO- on, v 0 "on.

X] I CH 0113/ 3 on I CH3" N i i J Y O: (XXI) (XXII) CH3 CH3 CH-OA0 CH:-O=Ac --OH "-OH o= T0113 30f: Torr X F CH3 CH on," CH

(XXI-V) (XXIII) GHQ-07R o=o CH3 ....OH

gill! XVII, XVIII, XIX, XXI, XXIII, XXIV (XXV) wherein M is hydrogen or an alkali-metal, X is a halogen having an atomic weight from 35 to eighty, inclusive, i.e., or iodide, X is hydrogen, fluorine or chlorine, R is chlorine or bromine, Ac is the acyl radical of a hydro- 70 hydrogen or the acyl radical of a hydrocarbon carb'oxylic carbon carboxylic acid containing from one to twelve caracid containing from one to twelve carbon atoms, inclujbOIl atoms, inclusive, X is a halogen having anatomic sive, and Y is fl-hydroxymethylene or carbonyl, i.e., weight from 35 to 127, inclusive, i.e., chlorine, bromine ll-subst ituent is ,B-hydroxy or keto. Lower-alkyl, -whe1'-' or iodine, X is a halogen having an atomic weight from h ever it appears means-containing from one to eight carbon nineteen to 127, inclusive, i.e., fluorine, chlorine, bromine 15 atoms, inclusive, e.g.,-methyl, ethyl, propyl, octyl;

The novel a and their 21-esters as defined hereinabove, and the corresponding 9a-chloro compounds, i.e., compounds represented by the following formulae and the corresponding A compounds:

| --OH You.

wherein X", Y and R have the values given hereinbefore,

. are anti-inflammatory agents with improved ratio of therapeutic activity to undesirable side effects, e.g., gastrointestinal disturbances, salt retention, edema, etc., known to exist with similar known physiologically active steroids. Many of the higher molecular weight esters, particularly the ones resistant to hydrolysis and/ or more insoluble in body fluids, provide compounds with prolonged activity over the corresponding 21-hydroxy compounds. The compounds named above are useful in the treatment of various inflammatory conditions of the skin, eyes, respiratory tract and the bones and internal organs due to bacterial or viral infections, contact dermatitis and allergic reactions and possess improved therapeutic ratios of antiinflammatory activity to undesirable side effects, compared to the corresponding compounds without the methyl group. For this purpose they may be incorporated in the various inert ointments, cremes, lotions and sprays well known in the art. They may be combined with any of the knownantibiotics, especially the penicillins, neomycin, tetracycline, chloromycetin and novobiocin. The corresponding 9m-chloro compounds of the present invention, have especial advantages, e.g., a better therapeutic ratio of anti-inflammatory to undesirable side-effects, e.g., catabolic activity.

Other of the compounds of the present invention, as well as being useful as intermediates in the production of the above-described compounds physiological activity, including glucocorticoid, mineralocorticoid and anti-inflammatory activity. Notable among these are compounds XX, XXI, XXII and the corresponding 21-hydroxy compounds of those having a 21-acyloxy group. Compound IV possesses useful progestational activity.

The novel compounds of the present invention are prepared from the known 1l-keto-lG-dehydroprogesterone (I) by the following reactions: The 3-keto group is selectively protected from reaction by conversion to a 3-ketal, e.g., ethylene ketal, 3-enol ether, e.g., methyl enol ether, or a 3-enamine, e.g., pyrrolidyl enamine, according to procedures well known in the art. The pyrrolidyl 3- enamine forms selectively but with the ketal and enolalso possess useful ether, the 20-keto group must first be protected protecting group. The 1l-keto-l6-dehydroprogesterone,

protected at the 3-position, illustratively in the formulae I by the 3-enamine (II), is then reacted with a methyl Grignard reagent,. preferably methyl magnesium bromide or iodide, in the presence of a 1,4-addition promoting re-- produce 1l-keto-16a-methylprogesterone, still protected at i the 3-position, illustratively with a 3-enarnine (I11). The

3-protecting group is then hydrolyzed, e.g., with aqueous acid or base, to produce 1l-keto-16a-methylprogesterone (IV).

Alternatively, 16a-methylprogesterone (Ia) Marker et al., J. Am. Chem. Soc., 1289 (1942), is ll-oxygenated with a species of fungus which introduces an llaor 1113- 'hydroxy group to produce ll-hydroxy-16ot-methylprogesterone (IIa) which is then oxidized, in the same manner that 1111- or llB-hydroxyprogesterone has been oxidized to ll-ketoprogesterone, to produce ll-keto-la-methylprogesterone (IV).

1l-keto-l6u methylprogesterone is converted to 3,11- diketo-16a-methyl-4,17 (20) -pregnadien-21-oic acid loweralkyl ester in the manner described in US. Patent No. 2,790,814 for the conversion of ll-ketoprogesterone to 3,11-diketo-4,17(20)-pregnadien-2l-oic acid methyl ester, i.e., the 1l-keto-16 t-methylprogesterone is reacted with more than two molar equivalents each of an alkyl diester of oxalic acid,.preferably methyl or ethyl oxalate, and a base, preferably sodium methoxide or ethoxide or potassium tertiary butoxide, to produce the alkali-metal dienolate of 2,2l-dialkoxyoxalyl-1l-keto-l6u-methylprogesterone (V, M=alka1i-metal). This compound, or the free enol prepared by reaction of the alkali-metal dienolate with acetic acid (V, M=H), is then trihalogenated with chlorine or bromine, preferably the latter, to produce 2,21-d-ialkoxyoxalyl-2,21,21-trihalo 11 keto 16amethylprogesterone (VI). This compound rearranges with strong base, e.g., an alkali-metal alkoxide, in the presence of an alkanol, e.g., sodium methoxide or ethoxide in methanol or ethanol, to produce 2-halo-3,1l-diketo- 16w-methyl-4,l7(20)-pregnadien-21-oic acid alkyl ester (VII). The 2-halo group is removed by zinc and acetic acid or other, halogen removing agent to produce 3,11- diketo-l6tx-methyl-4,l7(20)-pregnadien-21-oic acid alkyl ester (VIII). This compound is a valuable intermediate in the production of a wide variety of l6-rnethyl steroids.

Conversion of 3,11-diketo-16a-methyl-4,l7(20)-pregnadien-Zl-oic acid alkyl ester to 11,3,21-dihydroxy-l6amethyl-4,17(20)-pregnadien-3-one (XI) is accomplished in themanner described in US. Patents 2,715,621, 2,781,- 343 and 2,790,814 for the conversion of 3,1l-diketo-4,l7 (20)-pregnadien-2l-oic acid alkyl ester to 115,21-dihydroxy-4,l7(20)-pregnadien-3-one, i.e., protecting the 3-keto group by a ketal, e.g., ethylene ketal, or preferably with an enamine, e.g., the 3-pyrro1idyl enamine as illustratively shown by Formula IX, and then reducing the ll-keto group and the 2l-carboxylic acid ester group with lithium aluminum hydride, sodium aluminum hydride or other reagent capable of such reductions without affecting the double bonds, to produce llfi,2l-dihydroxy-l6amethyl-4,17(20)-pregnadien-3-one, still protected at the 3-position, as illustratively shown by Formula X. The 3-keto protecting group is then removed by hydrolysis to produce 11B,21-dihydroxy-16a-methyl-4,17(20)-pregnadien-3-one (XI).

In the next step, l15,2l-dihydroxy-l6a-methyl-4,l7 (20)-pregnadien-3-one (XI) or a 2l-acylate thereof (XII) is condensed with a dialkyl estertof oxalic acid, preferably the methyl or ethyl ester, in the presence of an alkali-metal condensation catalyst, to produce an alkali-metal enolate of 2-alkoxyoxalyl-l16,21-dihydroxy- 16amethyl-4, 17 (20) -pregnadien-3 one (XiII, M: alkali:

from reaction. For this reason, the S-enarnine is the preferred 'metal) or a 2l-acylate thereof, respectively.

The reaction is usually conducted at between about room temperature and about 100 degrees centigrade. The alkali-metal condensation catalysts include the alkali-metal alkoxides,

the alkali-metals, alkali-metal amides, and alkyl alkalimetals, e.g., sodium methoxide, sodium ethoxide, potassium tertiary butoxide, finely dispersed sodium, triphenylmethyl sodium, etc. The alkali-metal alkoxides are preferred. Usually a slight excess of catalyst and a substantial excess of dialkyl oxalate are employed.

The thus produced alkali-metal enolate' (XIII) is then alkylated with a methyl halide, such as methyl iodide, to produce a 2-lower-alkoxy-oxalyl-2,16a-dimethyl-116, 2l-dihydroxy-4,17(20)-pregnadien-3-one or 2l-acylate (XIV). The usual alkylation conditions are employed. The alkali-metal enolate (XIII) may be used in situ in the reaction mixture where it was formed as described above or as the isolated, purified salt suspended in an inert solvent. r

In the next step, the 2-alkoxyoxalyl-2-methyl compound (XlV) is subjected to conditions whereby the alkoxyoxalyl group is removed, leaving the 2ot-methyl group, thus producing 2u,16a-dimethyl-11 3,2l-dihydroxy- 4,17()-pregnadien-3-one (XV) or a ZI-acylate thereof (XVI). The reversal of an acetoacetic ester type condensation in a disubstituted fi-ketoester is a recognized phenomenon. See Organic Reactions, Wiley Publishers, vol. I, 269 (1942), where alcoholic sodium ethoxide was reported to produce the reversal phenomenon.

The reversal step of the present invention is produced by the alkali-metal alkylation catalysts described above, in the presence of Water or a loWer-alkanol, i.e., the reversal is promoted by the presence of hydroxide or alkoxide ions, particularly methoxicle and ethoxide ions. Ordinarily, the 2l-oxy group of the compound produced in the reversal is a hydroxy group (XV) as the conditions which promote the reversal of the 2-carbonyl group also promote the alcoholysis of any 2l-acyloxy group to produce a 21-hydroxy. If the starting steroid for the condensation and/or alkylation step is a 2l-hydroxy group, then the reaction product of the reversal step will also be a 21-hydroxy group. The more hindered 2l-acy1oxy groups, e.g., trimethylacetoxy, 2,6-disubstituted'benzoyloxy, etc., will remain substantially intact during the reversal reaction whereas the unhindered groups, e.g., formoyloxy, acetoxy, and other lac-unsubstituted hydrocarbon acids, etc., are almost completely converted to hydroxy groups. The degree of alcoholysis or hydrolysis ofthe partially hindered 2l-acyloxy groups will depend, in part, upon the reaction temperature and time and reactants promoting the reversal.

The reaction product resulting from the reversal reaction will contain at least some 2,l6a-dimethyl-1l[3,21- dihydroxy 4,17 (20) pregnadiene-3-one and frequently free Zl-hydroxy steroid will be the predominant reaction product, e.g., if the starting steroid'is a 21-hydroxy compound.

It is preferred in the oxidative hydroxyla'tion of the reaction product of the reversal reaction that all the starting steroid for the axidative hydroxylation be 21- acyloxy steroid (XVI). The react-ion product (XV) is thus reacted with an esterification agent to protect the ZI-hydroxy group. The esterification is performed in the usual manner'employing an acid chloride or bromide or acid anhydride in pyridine or like amine, an acid in the presence of an esterification catalyst, or an ester under ester exchange reaction conditions. The thus-produced ester (XVI) is then oxidatively hydroxylated with osmium tetroxide and an oxidizing reagent, e.g., hydrogen peroxide, organic peracid, an amine oxide peroxide, or an aryl iodo oxide, in the manner described in US. Patents 2,769,825, 2,769,823 or in Hogg et al., I. Am. Chem. Soc., 77, 4436 (1955), to produce the corresponding 17a hydroxy 20 keto 2l-acyloxy compound (XVII), which can be hydrolyzed with base, e.g., sodium methoxide, sodium hydroxide, or sodium bicarbonate in methanol preferably While flushing with nitrogen to produce the ZI-hydroxy compound, i.e., 2a,16u-dimethyl- 11B,17a,2l-trihydroxy-4 pregnene-3,20-dione (XVIII), or oxidized with an N-haloamide or N-haloimide, e.g., N- bromoacetamide in pyridine or like amine, or with chromic acid or sodium dichromate, to produce the corresponding ll-keto compound (XIX). The latter compounds can also be hydrolyzed to produce the corresponding 21-hydroxy compounds.

Alternatively, instead of the hydrolysis or oxidation reactions described above, the compounds represented by Formula XVII can be converted to the corresponding 9a-halo compounds by the following sequence of reactions: The llfl-hydroxy group is dehydrated with any of the known dehydrating reagents employed in the dehydration of an ll-hydroxy group, but preferably an N- haloamide or N-haloimide in the presence of anhydrous sulfur dioxide or with thionyl chloride or methanesulfonyl chloride in pyridine, or by heating with toluenesulfonic acid in an organic solvent such as benzene, according to methods known in the art, to produce the corresponding 9(ll)-dehydro compound (XX). This compound is then reacted with hypochlorous, hypoiodous or hypobromous acid, prepared in the usual manner, e.g., with an N-haloamide or N-haloimide in the presence of aqueous perchloric acid, to produce the correspending 9a-halo-l1fi-hydroxy compound ()Qfl). Reaction of one of these latter compounds with a base, e.g., potassium acetate, yields the correspondingepoxy compound (XXII). This epoxy compoundis then reacted with aqueous or anhydrous hydrogen fluoride according to procedures known in the art to produce a 9m fluoro 115 hydroxy compound (XXIII) whose 21- acyloxy group can be hydrolyzed in the same manner as described above for the corresponding 9-hydrogen compounds to produce 2a,16u-dimethyl-9u-fluoro-11B,l7a,21- trihydroxy-4-pregnene-3,ZO-dione or oxidized to produce the corresponding ll-keto compounds (XXIV, X"=F).

The A steroids (XXV) otherwise corresponding to compounds XVII to XXIV, e.g., 2,16a-dim'ethyl-ll5,17u,

ZI-tr-ihydroxy-1,4-pregnadiene-3,20-dione and its 21- acetate, are prepared by dehydrogenation of the corresponding A compound (XVI, XVII, XVIII, XX, XXII, XXIH, XXIV, with a Fusarium [Experientia, 9, 371-372 (1953)] selenium dioxide or Septomyxa afiinis as described hereinafter. Alternatively, 2u,16u-dimethyl-11;3,17u,21-trihydroxy-4-pregnene-3,20-dione can be dehydrogenated as described above, converted to a 21-acylate, e.g., 21-acetate, and this compound then carried through the reactions described for the production of compounds XIX to XXIV, thereby producing the corresponding A compounds, as shown hereinafter.

The following examples are illustrative of the products and processes of this invention, but are not to be construed as limiting.

PREPARATION '1 1 1 -keto-1 6 a-methy l progesterone To a hot solution of 4.56 g. (0.014 mol) of 11-keto- 16-dehydroprogesterone in 45 n11. of methanol was added 2.25 ml. of pyrrolidine with swirling. The reaction product, the 3-pyrrolidyl enamine of 11-keto-16-dehydroprogesterone, soon separated as yellowish crystals. After cooling to five degrees, the mixture was filtered, the cake washed with cold methanol and' dried under vacuum. There was obtained 4.56 g. of 3-pyrrolidyl-3,5,16-pregnatriene-l1,20 dione melting at 154 to 169 C.

A solution of the thus-obtained enamine in milliliters of tetrahydrofuran was added slowly to a stirred suspension of 45 ml. of commercial three molar methyl magnesium bro'mide, 0.90 g. of cuprous chloride and 50 ml. of tetrahydrofupan. The mixture was cooled to room temperature and stirred under a nitrogen atmos phere for three hours. The excess Grignard reagent wascautiously destroyed by the dropwise addition of 30 ml. t water. To the mixture, containing 3-pyrrolidyl- 16a methyl-3,S-pregnadiene 11,20 dione, was added 18 ml. of acetic acid and 72 ml. of methanol and the mixture was warmed until a clear dark yellow solution was obtained. 72 ml. of a 10 percent aqueous solution of sodium hydroxide was added, bringing the pH to 8. The mixture was heated under reflux for 45 minutes. 4.5 ml. of acetic acid and 250 m1. of water were added and the cooled mixture was-extracted three times with methylene chloride. The combined extracts were washed with an aqueous sodium bicarbonate solution, water and then dried with sodium sulfate. The dried solution was evaporated and the residue, consisting essentially of 11- .keto-l6a-methylprogesterone, was dissolved in 400 ml. of

methylene chloride and chromatographed through a 200 g. column of magnesium silicate (Florisil). The column was developed with 400 ml. portions ofso lvent of the following composition and order: of hexanes (Skellysolvc B) plus 3 percent acetone, 5 of hexanes plus 5 percent acetone, 8 of hexanes plus 7 percent acetone, 5 of hexanes plus 10 percent acetone, 4 of hexanes plus percentacetone and finally, 1 of acetone. Fractions 9 to 25 (counting the methylene chloride fraction) were combined and recrystallized from a mixture of acetone and water to give 2.03 g. of ll-keto-lfiu-methylprogesterone melting at 179 to 182 C. A sample recrystallized from a mixture of ethyl acetate and hexanes melted at 183 to 185 C. had an [111 of plus 255 3),

A35 238 mu, a 15,850

11 a-lzydroxy-l 6 a-methylprogesterone Found To 16.6 1. of a fermentation medium consisting of 1.2

percent corn steep solids and two percent Cerelose 'glu-.

cose, adjusted to a pH of 4.8 to 5.0, was added an inoculum of Rhizopus nigricans minus strain, American type culture collection number 62271), and incubated for 24 hours at a temperature of 28 degrees centigrade using a rate of aeration of five percent air by volume per minute. To this medium containing a 24 hour growth of Rhizopus nigricans minus strain was added five grams of l6a-methylprogesterone in 150 milliliters of acetone to provide a suspension of the steroid in the culture. After an additional 24hour period of incubation under the same conditions of temperature and aeration, the beer and mycelium were extracted. The myce'lium was filtered, washed twice, each time with a volume of acetone approximately equal to the volume of the mycelium, and extracted twice, each time with a volume of methylene chloride approximately equal to the volume of the mycelium. The acetone and methylene chloride extracts including solvent were added to the beer filterate. The mixed extracts and beer filtrate were extracted successively with two one-half by volume portions of methylene chloride and then with two one-fourth by volume portions of methylene chloride. The combined methylene chloride extracts were washed with two one-tenth by volume portions of a two percent aqueous solution of sodium bicarbonate and then with two one tent'h by volume portions of water. After drying the methylene chloride extracts with about three to five grams of anhydrous sodium sulfate per liter of solvent and filtering, the solvent was removed by distillation. The residue was dissolved in 250 ml. of methylene chloride and chromatographed over a 500 g. column of magnesium silicate (Floris-i1). The column was developed with 5 1. of hexanes (Skellyso-lve B) plus 5 percent acetone, 10 l. of hexanesfplus 10 percent acetone, 5 l. of hexanes plus 25 percent ace-tone and 2 l. of acetone, in that order. The semicrysta'lline residues from the last 7 l. of hexanes plus 10 percent acetone, from all of the hexanes plus 25 percent acetone and the first liter of acetone eluate's were combined in methylene chloride and rechrom-atographed over 400 g. of magnesium silicate. This column was developed with 8 l. of hexanes plus 10 percent acetone, 8 l. of hexanes plus 15 percent acetone, 4 l. of hexanes plus 20 percent acetone, 4 l. of hexane's plus 25 percent acetone and 2,400 ml. of acetone, in thatorder. The residues from the last 4 l. of hexanes plus 10 percent acetone and the first 1,600 ml. of hexanes plus 15 percent acetone'eluates were combined and recrystallized twice from ethyl acetate to give 1let-hydroxy-Imus-methylprogesterone melting at 161 to 163 0., having an [111 of plus 149 in chloroformand the analysis below.

Calculated for C H 0 C, 76.70; H. 9.36 Found: C, 76.46; H, 9.63.

The last 4 l. of hexanes plus 15 percent acetone and the first 2,400 ml. of hexanes plus 20 percent acetone elutes containing 6,11u-dihydroxy-l6a-methylprogesterone which, when recrystallized from ethyl acetate, melted at 201 to 208 C., had an [04] of plus 82 in acetone and the analysis below.

Calculated for C H O C, 73.30; H, 8.95. Found: C. 73.30; H, 9.14.

V PREPARATION 3 1 1 -ket0-1 6 a-methylprogesterone with methylene chloride and .the combined methylene chloride solutions were washed successively with water, aqueous sodium bicarbonate and water. The washed solution was dried with sodium sulfate and then evaporated to dryness, leaving a residue of 11-keto-16a-methylprogesterone.

PREPARATION 4 3 ,1 1-dz'ket0-16a-methyl-4J7(20)-pregnadiene-21-0ic acid methyl ester A solution of 2.00 g. (5.8 mmol.) of 1l-keto-16amethylprogesterone in 30 ml. of dry tertiary butyl alcohol was warmed to C. and stirred under nitrogen. To the solution was added 3.2 ml. of ethyl oxalate and 3.03 g. of a 25 percent methanolic sodium methoxide solution. A yellow-green precipitate of the sodium dienol-ate of 2,2l-diethoxyoxalyl-ll-keto-16a-methylprogesterone appeared almost immediately.

The mixture was stirred for 20 minutes after which a cooled solution of 0.98 g. of anhydrous sodium acetate and 0.84 ml. of acetic acid in forty milliliters of methauol was added, thus producing the free dienol. solution was cooled to 0 C. and then treated dropwise with a cold solution of 2.0 g. of bromine in methanol over a period of ten minutes. There was thus produced 2,21,21 tribromo 2,21 diethoxyoxalyl 11 keto 16amethylprogesterone. p

The cooling bath was removed and to the solution was added 5.72 g. of a 25 percent methanolic sodium methoxide solution. The stirring was continued for 2.5 hours. There was thus produced 2-bromo-3,11-diketo-l6amethyl-4,l7(20)-pregnadien-2l-oic acid methyl ester.

To the resulting solution was then added five ml. of acetic acid and 1 g. of zinc dust and stirring was continued for thirty minutes. The mixture was filtered and the filtrate diluted with water and extracted thoroughly with methylene chloride. The extract wasdried with sodium sulfate and evaporated. The residue was dissolved in 400 milliliters of methylene chloride and poured over a 200-gram column of magnesium silicate (Florisil). The column was developed with 400 ml. portions of solvent of the following composition and order: 4 of hexanes (Skellysolve B) plus 5 percent acetone, of hexanes plus 7 percent acetone, 10 of hexanes plus 10 percent acetone and finally, 1 of acetone. Fractions 14 to 23 (counting the methylene chloride fraction) contained starting 1l-keto-l6e-methylprogesterone. Fraction 7 to 12 contained 3,11-diketo-16amethyl-4,17(20)-pregnadien-Zl-oic acid methyl ester which when recrystallized from methanol and water and then from methanol, melted at 177 to 184 C., had a XE; 23.5mp, a 26,200

PREPARATION 5 115,21 -dihydroxy-I 6a-methyl-4,1 7(20) -pregnadien-30ne A solution of 6.0 g. of 3,1l-diketo-16a-methyl-4, l7(20)-pregnadien-21-oic acid methyl ester, 6 ml. of pyrrolidine, and 180 ml. of para-toluenesulfonic acid in 120 ml. of benzene were heated at the reflux tempera ture of the mixture for one hour with the concomitant removal of the water of reaction. The solvent was distilled from the mixture to leave a residue consisting essentiannl of 3 pyrrolidiyl 16oz methyl 3,5,17(20)- pregnatrien-Zl-oic acid methyl ester.

This residue was dissolved in ml. of benzene and 10 ml. of ether, a suspension of 2.2 g. of lithium aluminum hydride in 350 ml. of ether was added thereto over a period of 5 minutes, and the mixture was stirred at room temperature for 1.5 hours. 20 ml. of ethyl acetate was added to destroy excess lithium aluminum hydride, followed by 30 ml. of water. The ether and benzene were distilled at reduced pressure from the mixture to leave a residue consisting essentially of 3-pyrrolidyl-l113, 21-dihydroxy-16a-methyl-3,5,17(20)-pregnatriene and inorganic material.

This crude distillation residue was mixed with 400 ml. of methanol at C. until solution was afiected. 70 ml. of an aqueous 5 percent sodium hydroxide solution was added thereto and heating of the mixture at about 40 C. was continued for 10 minutes. The solution was neutralized with acetic acid and the solvent distilled therefrom at reduced pressure and at a temperature below C. The residue was mixed with 100 ml. of water containing 10 ml. of concentrated hydrochloric acid, filtered and washed with water to give 11,8,21-dihydroxy- 16a-methyl-4,17(20)-pregnadien-3-one.

EXAMPLE 1 Z-ethoxyoxalyl-I1,8,21-dihydr0xy-16a-methyl-4, 1 7(20) [cis] -pregnadien-3-0ne A solution of 17.27 g. (0.05 mol.) of 1113,2l-dihydroxy- 16a-methyl-4,17(20)-pregnadien-3-one was prepared in 300 ml. of dry tertiary butyl alcohol by heating the mixture at 70 C. The solution was cooled to C. and to the stirred solution, protected from atmospheric oxygen by bubbling nitrogen therethrough, was added 14.6 g. (0.10 mol.) of ethyl oxalate followed by a solution of 4.05 g.

.(0.075 mol.) of sodium methoxide dissolved in 16 ml.

,the mixture then filtered. The pale yellow-green precipitate was washed and dried at room temperature in a 14 vacuum. The yield of about 24 g. of precipitate consisted primarily of the sodium enolate of 2-ethoxy-oxalyl-llfi, 21-dihydroxy-16a-methyl-4,17(20)-pregnadien-3-one.

The precipitate was dissolved in 250 ml. of water and l the solution acidified with dilute hydrochloric acid. The

resulting precipitate was collected by filtration, washed with water and dried. There was thus obtained an amorphous powder consisting essentially of 2-ethoxyoxalyl-11fi,

21 dihydroxy 16a. methyl 4,17(20) pregnadien 3- one, which gave a positive red-brown ferric chloride test.

' EXAMPLE 2 2 (1,1 6oc-dimethyl-1 1,B,21 -dihya'roxy4,1 7 (20)- pregnadien-.i-one A mixture of 4.70 g. of crude 2-ethoxyoxalyl-1lfl,21- 1 dihydroxy 16oz methyl 4,17(20) pregnadien 3 one, obtained according to the method of Example 1, 10 g. of anhydrous potassium carbonate, 15 ml. of methyl iodide and 100 ml. of acetone was stirred at about 25 C. for 40 hours. Water was then added and the mixture extracted thoroughly with methylene chloride. The extract was washed with water, dried and the solvent distilled to leave a glassy residue consisting essentially of Z-methyl-Z- ethoxyoxalyl 115,21 dihydroxy 16cc methyl 4, l7(20)-pregnadien-3-one.

The glassy residue was dissolved in 50 ml. of methanol to which was then added 3 ml. of a 25 percent solution of sodium methoxide in methanol. The now red solution was stirred for 2 hours at about 25 C. The mixture was then diluted with about 200 ml. of water and extracted thoroughly .with methylene chloride. The combined methylene chloride extracts were washed with water, dried and the solvent then distilled therefrom, leaving a steroid residue consisting essentially of 2a,16a-dimethyl-1lfl,21- dihydroxy-4,17(20)-pregnadien-3-one.

EXAMPLE 3 2a,]tie-dimethyl-l1,8,21-dihydr0xy-4J 7(20)- pregnadien-.i-one 21 -acetate The crude 2a,16a-dimethyl-11B,21-dihydroxy-4,l7(20)- pregnadien-3-one obtained from a reversal reaction performed exactly as described in Example 2 was dissolved in a mixture of 10 ml. of acetic anhydride and 10 ml. of dry pyridine. The mixture was maintained at about 25 C. for about 16 hours. The excess acetic anhydride was then decomposed with ice water-and the resulting gummy precipitate was extracted with benzene. The benzene solution was washed with cold dilute hydrochloric acid, cold aqueous sodium bicarbonate and finally with Water and then dried. The dried benzene solution was poured over a chromatographic column of 100 g. of magnesium silicate (Florisil'). The column was developed with 1,350 ml. of hexanes (Skellysolve B) containing 5 percent acetone followed by 750 ml. of hexanes plus 7.5 percent acetone and then 150 ml. of acetone. The eluates were collected in 150 :ml. fractions. The fractions containing the major proportion of the total solids consisted of crystalline 20,l6oc-dl1116l1hYl-l 15,21-dihydroxy-4,l7(20)-pregnadien-3-one 2l-acetate.

Similarly 2u,16a-dimethyl-1 1,8,21-dihydroxy-4,17 (20) pregnadien-3-one is converted, by esterification of the 21- hydroxy group, e.g., by reaction with the appropriate acid anhydride, acid chloride or bromide, ester by ester exchange, acid in the presence of an esterification catalyst, etc., to other 2a,16a-dimethyl-1lfl,21-dihydroxy-4,17(20)- pregnadien-3-one 21-acylates wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, e.g.,

formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, Z-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, tn'ethylacetic, heptanoic, octanoic, a-ethylisovaleric, a cyclic acid, e.g., cyclopropylideneacetic, a cycloaliphatic acid, e.g.,cyclopentylformic, cyclopentylacetic, B-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, fi-cyclohexylpropionic, an aryl or alkaryl acid,

e.g., benzoic, 2, 3, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic, 2,4,6- trimethylbenzoic, 2,4,6-triethylbenzoic, a-naphthoic, 3- methyl-tx-naphthoic, an aralkyl .acid, e.g., phenylacetic, phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acid, (which can be converted to water soluble, e.g., sodium, salts) e.g., succinic, glutaric, a-methylglutaric, fl-methylglutaric, etc.

EXAMPLE 4 2a,] 6a-dimethyl-1 119,1 7a,21-trihydroxy-4-pregnene- 3,20-dione 21 -ace tate To a solution of 1.40 g. (3.5 mmol.) of 20,160t-dlmethyl-1 1 8,21-dihydroxy-4, 17 (20) -pregnadiene-3-one 21- acetate in 70 ml. of dry tertiary butyl alcohol was added at room temperature 9 ml. of drypyridine, 5.8 ml. of dry tertiary butyl alcohol solution containing 1.37 g. (9.1 mmol.) of N-methylmorpholine oxide peroxide (US. 2,769,823), and 10 mg. of osmiumtetroxide, in that order. The resulting solution was stirred at between 25 and 30 C. for 18 hours. There was then added 150 ml. of water to the mixture which was then extracted thoroughly with .methylene chloride, the methylene chloride solution washed with water, cold dilute hydrochloric acid, cold aqueous sodium bicarbonate, water and then dried. The solvent was distilled from the dried solution at reduced pressure. The crude residue was dissolved in methylene chloride and poured over a column of 110 g. magnesium silicate (Florisil). The column was developed with 175 ml. portions of solvent of the following composition and order: 8 of hexanes (Skellysolve B) plus 10 percent acetone, 7 of hexanes plus 12 percent acetone, 2 of hexanes plus 15 percent acetone, and 1 of acetone. The hexanes plus 5 percent acetone eluted starting steroid. The fractions comprising the major peak of eluted solids contained 2a,16a-dimethyl-1 1,8,17a,2l-trihydroxy-4-pregnene- 3,20-dione 2l-acetate.

EXAMPLE 5 2a,] 6a-dimetIzyl-1 1,8,1 7 a,21 -trihydrxy-4-pregene 3,20-dione milliliters of water and refrigerated. The mixture was then filtered and the solids recrystallized from acetone Skellysolve B hexanes to give pure 2a,l6 x-dimethyl-1113,

' 17a,2 l -trihydroxy-4-pregnene-3 ,20-dione.

EXAMPLE 6 2,1 6a-dimethyl-1 13,1 701,21-trihydroxy-1,4-pregnadiene- 3,20-dione Septomyxa gflinis (A.T.C.C. 6737) was maintained on malt agar slants composed of 50 g. of dry malt extract, g. of Edamine enzymatic digest of lactalbumin, and 20 g. of agar diluted to 1 l. with tap water and adjusted to a pH between 6.5 to 7.0. Inoculum from the agar slant was transferred to 1 l. Erlenmeyer flasks containing 100 ml. of malt extract agar and incubated at room temperature for from 4 to 7 days to produce spores. The spores were suspended in 100 ml. of sterile one percent saline.

'5 ml. of this saline spore inoculum was introduced into each of 5 250 ml. flasks containing 100 ml. each of medium consisting of 1 percent Cerelose dextrose and 2 percent corn steep liquor of 60 percent solids which was adjusted to pH 4.8 to 5.0 with sodium hydroxide. These were incubated for 48 to 72 hours with shaking at room temperature and then added to six 1. of the same fermentation medium as described above. This culture was maintained for 24 hours at room temperature with aeration at the rate of 1 l. per minute. This 6 l. of seed culture was then added to 100 l of medium and grown at room temperaturefor 24 hours with agitation and aeration ata time with 12 l. of acetone, and then suspended and slurried twice, each time with 12.1. of methylene chloride. The thus-obtained acetone and methylene chloride mycelium extracts were pooled and added to the. extract obtained from four extractions of the filtered beer and water wash, each extraction being with 24 l. of methylene chloride. The extracts from the filtered beer and water wash and those from the mycelium were combined and washed twice, each time with 12 l. of 2 percent sodium bicarbonate solution and then twice, each time with 12 l.

of Water. The Washed extract was concentrated in a still 7 to give 3 1. of concentrate which was then evaporated to dryness on a steam bath in air to give a crude crystalline residue. This residue was triturated 6 times, each time with 25 ml. of diethyl ether. The remaining crystals were dissolved in 250 ml. of hot methanol, filtered, and cooled to give crystals of 2,16u-dimethyl-11B,17a,21-trihydroxy- 1,4-pregnadiene-3,20-dione.

- EXAMPLE 7 2,1 6a-dirnethyl-1 1 8,1 7:1,21-trihydroxy-1,4-pregnadiene- 3,20-dione ZI-acetate Following the procedure of Example 3, but substituting one gram of 2,16a-dimethyl1l/3,17a,21-trihydroxy- 1,4-pregnadiene-3,20-dione as starting steroid, there was produced 2,16a-dimethyl-l1fl,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 2l-acetate.

Other 2l-esters of 2,l6u-dimethyl-1lfi,l7a,2l-trihydroxy-1,4-preguadiene-3,ZO-dione and of 2a,16a-dimethyl- 11B,17u,21-trihydroxy-4-pregnene-3,20-dione are prepared in the manner described in the paragraph following Example 3.

EXAMPLE 8 2 (1,1 6a-dimethyl-1 :,21-trihydr0xy4-pregene- 3,11,20-tri0ne 21-acetate To a solution of 2.5 mmol. of 2a,16oz-dln1thYl-11B, 170,2l-trihydroxy-4-pregnene-3,ZO-dione 2l-acetate and 2 ml. of pyridine in ml. of tertiary butanol was added 500 mg. of N-bromoacetamide. The reaction mixture was maintained at room temperature for about 16 hours whereupon the solution was diluted with 50 ml. of water containing 500 mg. of sodium sulfite, and the mixture was then concentrated at reduced pressure to about 40 ml. The distillation residue was refrigerated, filtered, and the filter cake was washed with water and then dried. It consisted of 2a,16a,dimethyl-17a,21-dihydroxy-4-pregnene- 3,11,20-trione 21-acetate.

Following the procedure of Example 8, but substituting 1 7 droxy-1,4-pregnadiene-3,-11,20-trione and of 2u,16a-dimethyl-l7a,21-dihydroxy-4-pregnene 3,11,20 trione, respectively.

EXAMPLE 9 2 11,1 6u-dimethyl-1 7a,21 dihydroxy-4,9(11 -pregnadiene- 3,20-dine 21 -acetate To a solution of 8.5 g. of 2a,-16adimethyl-l1,8,17a,21- trihydroxy-l6oc-methyl-4-pregnene-3,20-dione 21 acetate in 42.5 ml. of pyridine was added 5.63 g. of N-hromoacetamide. After standing at room temperature for a period of 15 minutes, the reaction solution was cooled to to 10 C. and, with shaking, sulfur dioxide gas was passed over the surface until the solution gave no color with acidified starch-iodide paper. During the addition of sulfur dioxide gas, the reaction became warm. The temperature was kept under 30 C. by external cooling and by varying the rate of sulfur dioxide addition. Thereafter to the reaction mixture was added 400 ml. of ice water and the resulting precipitate collected by filtration.

This material was recrystallized from acetone-Skellysolve B hexanes to give 2a,16u-dimethyl-l7a,21-dihydroxy-4, '9 l 1 )-pregnadiene-3,20-dione 21-acetate.

Following the procedure of Example 9, but substituting 2,16rx-dimethyl11,3,17u,21-trihydroxy 1,4 pregnadiene- 3,20-dione Ill-acetate as the starting compound, there is thus produced 2,16a-methyl-17a,2l-dihydroxy-1,4,9( 11 pregnatriene-3,20-dione ZI-acetate.

Similarly, substituting another 21-acylate of 2,16a-dimethyl-11,8,l7a,21-trihydroxy-1,4-pregnadiene 3,20 dione or a 2l-acylate of 2ct,16a-dimethyl-11B,17a,21-trihydroxy-4-pregnene-3,ZO-dione wherein the acyl radical is, e.g., that of an acid named in the paragraph following Example 3, as the starting compound in the dehydration reaction described in Example 9, there is thus produced the corresponding 21-acy1ate of 2,16a-dimethyl-17a,21- dihydroxy-1,4,9(11)-pregnatriene-3,2 O-dione and of 20:, 16a-dimethyl-17a,21-dihydroxy-4,9( 1 1 -pregnadiene-3,20- dione, respectively.

EXAMPLE 1O To a solution of 5.9 g. of 2a,.16a-dimethy1-17a,21-dihydroxy-4,9(11)-pregnadiene-3,20-dione 21-acetate in 100 ml. of methylene chloride and 250 ml. of tertiary butyl alcohol was added a solution of 14 ml. of 72 percent perchloric acid in 100 ml. of water followed by a solution of 2.34 g. of N-bromo-acetamide in 60 ml. of tertiary butyl alcohol. After stirring the reaction mixture for 15' minutes, a solution of 2.8 g. of sodium sulfite in 140 ml. of water was added and the reaction mixture was concentrated to a volume of about 500 ml. under reduced pressure at about 40 C. At this point crystallization started.

The concentrate was cooled in an ice bath and while stirring 500 ml. of water was added. After stirring for a period of one hour, the crystalline product was isolated by filtration, the crystals were washed with water and airdried to give 2a,16m-dimethyl-9a-bromo-11fl,17a,21-trihydroxy-4-pregnene-3,20-dione 21-acetate.

Following the procedure of Example 10, but substituting 2,16a-dimethyl-17m,21-dihydroxy-1,4,9(l1)-pregnatriene-3,20-dione 21-acetate as the starting compound, there is thus produced 2,16u-dimethyl-9a-bromod lfi,-17a,21-1I1'ihydroxy-1,4-pregnadiene-3,20-dione 21-acetate.

Similarly, substituting another 21-acylate of 2,16a-dimethyl-170:31-dihydroxy-l;4,9( l l) pregnatn'ene 3,20- dione or a 21-acylate of 2a,16a-dimethyl-17a,2l-dihydroxy-4,9(1 1)-pregnadiene-3,20-dione wherein the acyl radicalis, e.g., that of an acid named in the paragraph following Example 3, as the starting compound in the reaction described in Example 10, there is thus produced the corresponding 21-acylate of 2,l6a-dimethyl-9ubromo- 115,16u,-21-t1ihydroxy-1,4-pregnadiene-3,20-dione and of :,16a-di1116thYI-9u bromo llfi,17oz,2l trihydroxy 4- pregnene-3,20-dione, respectively.

Substituting N-chl-orosuccinimide for the N-bromoacetamide in the reaction described in Example 10 and the paragraph following is productive of the corresponding 9a-chloro compounds, e.g., 2,16ri-methyl-9a-chloro-11B, 17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 21 acetate and 2u,16u-dimethy119u-chlorod1,3,17a,21-trihydroxy 4- pregnene-3,20-dione 21-acetate.

EXAMPLE 11 To a solution of 6.78 g. of 2a,16a-dimethyl-9a-bromo- 11fl',17u,21 trihydroxy-4-pregnene-3,20-dione 21-acetate in 175 ml. of acetone was added 6.78 g. of potassium acetate and the resulting suspension was heated under reflux for a period of seventeen hours. The mixture was then concentrated to approximately 60 ml. of volume at reduced pressure on the steam bath and thereupon diluted with water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was redissolved in methylene chloride and chromatographed over 200 g. of magnesium silicate (Florisil). The column was eluted with 1 l. per-- tions of hexnaes (Skellysolve B) containing increasing proportions of acetone. There was thus eluted 2a,16adimethyl 93,1113 epoxy-17a,-21-dihydroxy-4-pregnene- 3,20-dione ZI-acetatae which was freed of solvent by evaporation of the eluates.

Following the procedure of Example 11, but substitut ing 2,16a dimethyl-9a-bromo-11,8,17a,21-trihyroxy-l,4- pregnadiene-3,20-dione 21-acetate as the starting compound, there is thus produced 2,16a-dimethyl-9fi,11/3- epoxy 17a,21-dihydroxy-1,4-pregnadiene-3,20-dione 2lacetate.

4 Similarly, substituting another 21-acylate of 2,16u-dimethyl 90c bromo 11,8,17a-21-trihydroxy-1,4-pregnadiene-3,20-dione or a 21-acylate of 2a,16a-dimethy1-9abromo 11;3,17oz,21 trihydroxy-4-pregnene-3,20-dione wherein the acyl radical is, e.g., that of an acid named in the paragraph following Example 3, as the starting compound in the reaction described in Example 11, there is thus produced the corresponding 21-acylate of 2,160:- dimethyl 95,11 8 epoxy-17a,21-dihydroxy-1,4, pregnadiene-3,2O dione and of 2a,16u-din1ethyl-9 8,11/3-epoxy- 17,21-dihydroxy-4-pregnene-3,20-dione, respectively.

EXAMPLE 12 2 11,1 6 a-dz'm'ethyl-9a-flu0r0-1 16,1 7 0:,21 -trihydr0xy-4 pregn ens-3 ,2 O-dione 21 -acetate To approximately 1.3 g. of hydrogen fluoride contained in a polyethylene bottle and maintained at 60 C. was added 2.3 ml. of tetrahydrofuran and then a solution of 500 mg. of 2a,16c:-dimethyl-9B,l1;8-epoxy-17oz,21dihydroxy 4 pregnene-3,20-dione 21-acetate in 2 ml. of methylene chloride. The steroid solution was rinsed in with an additional 1 ml. of methylene chloride. The light red colored solution was then kept atapproximately 30 C. for 1 hour and at 10 C. for 2 hours. At the end of this period it was mixed cautiously with an excess of cold sodium bicarbonate solution and the organic material extracted with the aid of additional methylene chloride. The combined extracts were washed i with water, dried over anhydrous sodium sulfate and concentrated to approximately 35 ml. of volume. This solution was chromatographed over forty milliliters of magnesium silicate (Florisil). The column was developed with 500 ml. portions of hexanes (Skellysolve B) containing increasing proportions of acetone. There was thus eluted 2a,16u dimethyl-9a-fluoro-11fi,17a,21-trihydroxy-4pregnene-3,20-dione 21-acetate which was freed of solvent by evaporation of the eluate fractions.

Following the procedure of Example 12, but substituting 2,160: dimethyl 95,1IB-epoxy-17u,21-dihydroxy- 1,4-pregnadiene-3,20-dione 21-acetate as the starting com- 19 pound, there is thus produced 2,16u-dimethyl-9a-fiuoro- 11,8,170:,21 trihydroxy 1,4 pregnadiene-3,20-dione 21- acetate.

Similarly, substituting another 21-acylate of 2,160z-(llmethyl 9,8,11/3 epoxy 170:,2l-dihydroxy-1,4-pregnardiene-3,20dione or a 21-acylate of 20:,160:-dirnethyl- 9 8,115 epoxy 170:,21-dihydroxy-4-pregnene-3,ZO-dione wherein the acyl radical is, e.g., that of an acid named in the paragraph following Example 3, as the starting compound in the reaction described in Example 12, there is thus produced the corresponding 21-acylate of 2,160:- dimethyl 90: fluoro-115,170:,21-trihydroxy-1,4-pregnadiene 3,20 dione and of 20:,160t-dimethyl-9a-fluoro- 11,9,170:,21 trihydroxy 4-pregnene-3,2O dione, respectively.

EXAMPLE 13 20:,160:-dimethyl-90:-flu0ro-1 70:,21-dihydr0xy-4- pregnene-3,11,20-frine 21 -acetate Following the procedure of Example 13, but substituting 2,160: dimethyl 90: fluoro-11p,170:,21-trihydroxy- 1,4-pregnadiene-3,20-dione 21-acetate as the starting Com pound, there is'thus produced 2,160:-dimethy1-90:-fluoro- .170:,2l dihydroxy 1,4-pregnadiene-3,l1,20-trione 21- acetate. Similarly, substituting another 21 acylate of 2,160:- dimethyl 90: fluoro 11B,170:,21-trihydroxy-1,4-pregnadiene-3,20-dione or a 21-acylate of 20:, 160:-dimethyl-.

90: fluoro 11 9,170:,21 trihydroxy 4 pregnene 3,20- dione wherein the acyl radical is, e.g., that of an acid named in the paragraph :following Example 3, as the starting compound in the oxidation reaction described in Example 13, there is thus produced the corresponding 21- acylate of 2,160t-dimethyl-90:-fluoro-l70:,21-dihydroxy-1,4- pregnadiene-3,11,20-trione and of 20:,160:-dimethyl-90:- fluoro 17 0:,21 dihydroxy-4-pregnene3,11,20-trione, respectively.

EXAMPLE 14 3.25 g. of 20:,160:-dimethyl'90:-fluoro-1lfl,l70:,21-trihydroxy-4-pregnene-3,20-dione 21-acetate were dissolved in 325 ml. of methanol, previously purged of air-oxygen by passing nitrogen through it for 10 minutes, and thereto was added a solution of 1.63 g. of potassium bicarbonate in 30 ml. of water, similarly purged of oxygen. The mixture was allowed to stand at room temperature for a period of 5 hours in a nitrogen atmosphere, thereupon neutralized with 2.14 ml. of acetic acid in 40 ml. of water. Themixture was concentrated to approximately /3 vol- -ume at reduced pressure on a 60 C. water-bath. Thereupon 250 ml. of water was added and the mixture chilled. The crystalline product was collected on a filter, washed with water and dried to give 20:,l6a-dimethyl-9a-fluoro- 11 3,170:,21-trihydr0xy-4-pregene-3,2O dione.

Following the prooedureof Example 14, but substituting 2,160: dimethyl 90:-fluoro-1l,B,l7o:,2l-trihydroxy- 1,4-pregnadiene-3,20-dione 21-acetate as the starting compound, there is thus produced 2,160:-dimethyl-90:-fluoro- 1 1B,170:,21-trihydroxy-1,4-pregnadiene-3,20-dione.

3 Similarly, 20:,160: diethyl-9a-fluoro-170:-21-dihydroxy- 4-pregnene-3,11,20-trione 21-aeetate is hydrolyzed to 29 20:,160: dimethyl fluoro :,2l-dihydroxy-4-pregnene-3,11,20-trione and 2,160t-dimethyl-90:-fluoro-170:,21- dihydroxy 1,4 pregnadiene- 3-1 1,20-trione 21-acetate is hydrolyzed to 2,160:-dimethyl-90:-fluoro-170:,21-dihydroxy- 1,4-pregnadiene-3,11,20-trione.

EXAMPLE 15 w A solution was prepared containing 50 mg. of 2,160:- dimethyl 90: fluoro-1118,170:,2l-trihydroxy-4-pregnene 3,20-dione in 1 ml. of pyridine and 1 ml. of propionic anhydride. The solution was allowed to stand at room temperature for a period of 21 hours and was then poured into 10 ml. of water. The reaction mixture was then extracted with 3 10 ml. portions of methylene chloride, the methylene chloride extracts were combined, washed with .water, dried over anhydrous sodium sulfate and evaporated to give a residue of 2u,160:-dimethy1-9u:-fiuoro- 11B,170:,21 trihydroxy-4-pregnene-3,20-dione 21-propionate.

Following the procedure of Example 15, but substituting 2,160: dimethyl-9a-fl-u0ro-11B,170:,21-trihydroxy-1,4- pregnadiene-3,20-dione as starting compound, there is thus produced 2,160:-dimethyl-90:-fluoro-1 1fi,l7a,21-trihydroxy- 1,4-pregnene-3,20-dione 21-propionate.

Similarly, 2,160: dimethyl-9m-fluoro-170:,21-d1hydroxy- 1,4-pregnadiene-3,11,20 trione is converted to 2,160:-dimethyl 90: fluoro 170:,21- dihydroxy 1,4-pregnadiene 3,11,20 trione 21 propionate and 20:,160: dirnethy-l 90: fluoro 170:,2l-dihydroxy 4 pregnene- 3,11,20-trione is converted to 20:,l6u-dimethyl-9u-fluoro- 170:,21-dihydroxy-4-pregnene-3,11,20 trione 21 propionate.

Similarly, substituting another acylating agent for the propionic anhydride in the esterification of 2,160:-di-

methyl 90:-fluoro-1 1B,170:,21-trihydroxy-1,4-pregnadiene- 3,20-dione or 20:,16o:-dimethyl-90:-fiuoro-11B,170:,21-trihydroxy-4-pregnene-3,20-dione, e.g., in the manner described in the paragraph following Example 3, there is thus produced other 21-acylates of 2,160:-di methyl-90t-fluoro 115, 170: 21 trihydroxy 1,4-pregnadiene-3,20-dione and of 20:,160: dimethyl-9a-fluoro-11,6,170:,21-trihydroxy-4-preg nene-3,20-dione,respectively, wherein the acyl radical is,

e.g., that of an acid named in the paragraph following Example 3. The corresponding ll-keto compounds are similarly converted to their coresponding 21-acylate esters.

We claim: 1. A compound having the formula CHzOR mmfiam. lQU

(References on following page) 21 References Cited by the Examiner UNITED STATES PATENTS 2,852,538 9/1958 Scheri et a1. 260397.45

OTHER REFERENCES Arth et a1.: J. Am. Chem. Soc., vol. 80 (June 20, 1958), pages 3160 and 3161.

Arth et 211.: J. Am. Chem. Soc., vol. 80 (June 20, 1958), pages 3161-3163.

Hogg et 211.: I. Am. Chem. Soc., vo1. 77 (December 5, 1955), pages 6401 and 6402.

- Marker et 211.: I. Am. Chem. Soc., vol. 64 (1942), pages 128021116 1281.

22 Oliveto et 21.: J. Am. Chem Soc., vol. 80 (August 20, 1958), page 4428.

Oliveto et a1.: 1. Am. Chem. Soc., vol. 80 (August 20, 1958), Page 4431.

Robinson et al.: J. Am. Chem. Soc. vol. 81 (Jan. 20,

1959), pages 408-410'(p. 408 necessary).

10 LEWIS GOTTS, Primary Examiner.

B. E. LANHAM, LESLIE H. GASTON, MORRIS LIEB- MAN, Examiners. 

1. A COMPOUND HAVING THE FORMULA 